HIV Replication and Persistence in T Follicular Helper Cells

Following up on the recent post on T follicular helper cells
(TFH), a study published on December 17th in the Journal of Experimental Medicine reports that TFH represent a major site of HIV replication and
persistence. The finding is not necessariy surprising, because lymph node studies
conducted in the late 1980s and early 1990s showed that CD4 T cells in areas named germinal centers bore a great
burden of HIV infection, and it is now known that this is where TFH locate during
an immune response. But it was not previously understood that these CD4 T cells comprise a discrete subset, and TFH are now becoming
increasingly well characterized in terms of both identifying features (such as
surface markers and cytokine secretion) and their function in providing help to
B cells.

Matthieu Perreau and colleagues from the University of
Lausanne investigated TFH in three different groups of HIV-positive
individuals:

A control group of 13 HIV-negative individuals was also
included. The study confirmed the prior finding that TFH are significantly
expanded in the lymph nodes of people with HIV compared to controls and that
this expansion correlates with alterations in B cell subsets (a decline in
long-lived resting naïve and memory B cells and an increase in short-lived
activated B cells). The percentage of TFH correlated significantly with peripheral
blood HIV viral load (r=0.6035, p=0.002). Suppression of HIV replication by ART
reduced TFH levels and shifted B cell subsets back toward the distribution observed
in controls. Echoing and extending the previous research by Madelene Lindqvist,
a substantial proportion of the TFH were found to be specific for HIV, with
responses to Gag and Pol proteins more commonly detected than those against Env
(based on a test evaluating cytokine production after stimulation with Gag, Pol
or Env peptides).

An analysis of the different CD4 T cell populations present
in lymph nodes revealed that TFH contained the greatest amount of HIV DNA: assuming 1 HIV DNA copy per cell, approximately 5% of the TFH population was
infected. After 72 weeks of ART there was a 1.5-2 log drop in the number of TFH
containing HIV DNA, but a reservoir of infected cells remained detectable. Cell
culture experiments showed that TFH were highly susceptible to HIV infection
and replication compared to other CD4 T cell subsets, with the difference being
most notable among the LTNP. The expression of the proliferation marker Ki67 by
TFH was found to correlate with HIV DNA levels and ability to support HIV replication
in vitro. Consistent with the elevation in immune activation that occurs in
HIV, the proportion of TFH expressing Ki67 was 50% higher in the untreated
HIV-positive individuals compared to HIV-negative controls.

The discussion section of the paper highlights several
implications of the results, including:

HIV itself -- as opposed to other potential
factors, like microbial translocation -- appears to be the main driving force
behind TFH activation and expansion, and the associated dysregulation of B
cells.

The preferential infection of TFH likely
contributes to viral persistence, because germinal centers have been shown to
offer limited access to CD8 T cells (which might otherwise kill HIV-infected
cells). Follicular dendritic cells in lymph nodes have also long been
known to be sites of extensive trapping of HIV virions, providing an ongoing
source of viruses to infect TFH.

The involvement of TFH in responses to new pathogens
and vaccines offers an explanation for the reported association between
intercurrent infections and vaccinations and transient HIV viral load increases
(activation of TFH by these stimuli provides additional targets for HIV
replication).

The expression of certain cell surface markers (such as PD-1) by
TFH may offer a means of targeting this population with interventions designed
to reduce HIV persistence. A human trial of an antibody targeting PD-1 is currently in the works
at the AIDS Clinical Trials Group (for more background see this recent short review "Novel Approaches to Curing HIV" by the principal investigator for the trial, Hiroyu Hatano).

This article was provided by Treatment Action Group. It is a part of the publication Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog.

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